tbuckley/cabot-search huggingface dataset:
Post hoc analysis of SUSTAIN 6 and PIONEER 6 trials suggests that people with type 2 diabetes at high cardiovascular risk treated with semaglutide experience more stable kidney function compared with placebo
Authors: Katherine R. Tuttle, Heidrun Bosch-Traberg, David Z.I. Cherney, Samy Hadjadj, Jack Lawson, Ofri Mosenzon, Søren Rasmussen, Stephen C. Bain
Journal: Kidney International (2023)

Glucagon-like peptide-1 receptor agonists reduce albuminuria and may stabilize the estimated glomerular filtration rate (eGFR) in people with type 2 diabetes (T2D). In this post hoc analysis of the SUSTAIN 6/PIONEER 6 trials encompassing 6480 participants at high cardiovascular risk (semaglutide, 3239 participants; placebo, 3241 participants), we investigated the effects of semaglutide versus placebo on eGFR decline. Pooled data by treatment were evaluated for annual eGFR change (total annual eGFR slope in ml/min per 1.73 m2) from baseline to end of treatment and time to persistent eGFR reductions of 30%, 40%, 50% and 57% or more, including subgroup analyses by baseline eGFR (30 to under 60 or 60 and over ml/min per 1.73 m2). In the overall population, the estimated treatment difference (ETD; semaglutide versus placebo) in annual eGFR slope was significant at 0.59 ml/min per 1.73 m2 (95% confidence interval 0.29; 0.89). The ETD was numerically largest in the 30 to under 60 ml/min per 1.73 m2 eGFR subgroup, 1.06 ml/min per 1.73 m2 (0.45; 1.67), but no significant interaction was observed for treatment effect by subgroup. Hazard ratios (semaglutide versus placebo) for time to persistent eGFR decline were under 1.0 for all eGFR thresholds in the overall population; and were numerically lower in the baseline eGFR 30 to under 60 ml/min per 1.73 m2 subgroup versus the overall population, although no significant interaction was observed for treatment effect by subgroup. Thus, pooled analyses of clinical trial data in patients with T2D suggest that semaglutide may reduce the rate of eGFR decline.
Systemic GDF11 attenuates depression-like phenotype in aged mice via stimulation of neuronal autophagy
Authors: Carine Moigneu, Soumia Abdellaoui, Mariana Ramos-Brossier, Bianca Pfaffenseller, Bianca Wollenhaupt-Aguiar, Taiane de Azevedo Cardoso, Claire Camus, Aurélie Chiche, Nicolas Kuperwasser, Ricardo Azevedo da Silva, Fernanda Pedrotti Moreira, Han Li, Franck Oury, Flávio Kapczinski, Pierre-Marie Lledo, Lida Katsimpardi
Journal: Nature Aging (2023)

Cognitive decline and mood disorders increase in frequency with age. Many efforts are focused on the identification of molecules and pathways to treat these conditions. Here, we demonstrate that systemic administration of growth differentiation factor 11 (GDF11) in aged mice improves memory and alleviates senescence and depression-like symptoms in a neurogenesis-independent manner. Mechanistically, GDF11 acts directly on hippocampal neurons to enhance neuronal activity via stimulation of autophagy. Transcriptomic and biochemical analyses of these neurons reveal that GDF11 reduces the activity of mammalian target of rapamycin (mTOR), a master regulator of autophagy. Using a murine model of corticosterone-induced depression-like phenotype, we also show that GDF11 attenuates the depressive-like behavior of young mice. Analysis of sera from young adults with major depressive disorder (MDD) reveals reduced GDF11 levels. These findings identify mechanistic pathways related to GDF11 action in the brain and uncover an unknown role for GDF11 as an antidepressant candidate and biomarker.
Unique progerin C-terminal peptide ameliorates Hutchinson–Gilford progeria syndrome phenotype by rescuing BUBR1
Authors: Na Zhang, Qianying Hu, Tingting Sui, Lu Fu, Xinglin Zhang, Yu Wang, Xiaojuan Zhu, Baiqu Huang, Jun Lu, Zhanjun Li, Yu Zhang
Journal: Nature Aging (2023)

Abstract An accumulating body of evidence indicates an association between mitotic defects and the aging process in Hutchinson–Gilford progeria syndrome (HGPS), which is a premature aging disease caused by progerin accumulation. Here, we found that BUBR1, a core component of the spindle assembly checkpoint, was downregulated during HGPS cellular senescence. The remaining BUBR1 was anchored to the nuclear membrane by binding with the C terminus of progerin, thus further limiting the function of BUBR1. Based on this, we established a unique progerin C-terminal peptide (UPCP) that effectively blocked the binding of progerin and BUBR1 and enhanced the expression of BUBR1 by interfering with the interaction between PTBP1 and progerin. Finally, UPCP significantly inhibited HGPS cellular senescence and ameliorated progeroid phenotypes, extending the lifespan of Lmna G609G/G609G mice. Our findings reveal an essential role for the progerin-PTBP1-BUBR1 axis in HGPS. Therapeutics designed around UPCP may be a beneficial strategy for HGPS treatment.
Phosphoinositide acyl chain saturation drives CD8+ effector T cell signaling and function
Authors: Joy Edwards-Hicks, Petya Apostolova, Joerg M. Buescher, Hannes Maib, Michal A. Stanczak, Mauro Corrado, Ramon I. Klein Geltink, Maria Elena Maccari, Matteo Villa, Gustavo E. Carrizo, David E. Sanin, Francesc Baixauli, Beth Kelly, Jonathan D. Curtis, Fabian Haessler, Annette Patterson, Cameron S. Field, George Caputa, Ryan L. Kyle, Melanie Soballa, Minsun Cha, Harry Paul, Jacob Martin, Katarzyna M. Grzes, Lea Flachsmann, Michael Mitterer, Liang Zhao, Frances Winkler, David Ali Rafei-Shamsabadi, Frank Meiss, Bertram Bengsch, Robert Zeiser, Daniel J. Puleston, David O’Sullivan, Edward J. Pearce, Erika L. Pearce
Journal: Nature Immunology (2023)
A value-based deep reinforcement learning model with human expertise in optimal treatment of sepsis
Authors: XiaoDan Wu, RuiChang Li, Zhen He, TianZhi Yu, ChangQing Cheng
Journal: npj Digital Medicine (2023)

Abstract Deep Reinforcement Learning (DRL) has been increasingly attempted in assisting clinicians for real-time treatment of sepsis. While a value function quantifies the performance of policies in such decision-making processes, most value-based DRL algorithms cannot evaluate the target value function precisely and are not as safe as clinical experts. In this study, we propose a Weighted Dueling Double Deep Q-Network with embedded human Expertise (WD3QNE). A target Q value function with adaptive dynamic weight is designed to improve the estimate accuracy and human expertise in decision-making is leveraged. In addition, the random forest algorithm is employed for feature selection to improve model interpretability. We test our algorithm against state-of-the-art value function methods in terms of expected return, survival rate, action distribution and external validation. The results demonstrate that WD3QNE obtains the highest survival rate of 97.81% in MIMIC-III dataset. Our proposed method is capable of providing reliable treatment decisions with embedded clinician expertise.
IFNγ binding to extracellular matrix prevents fatal systemic toxicity
Authors: Josephine Kemna, Evelyne Gout, Leon Daniau, Jessica Lao, Kristoffer Weißert, Sandra Ammann, Ralf Kühn, Matthias Richter, Christine Molenda, Anje Sporbert, Dario Zocholl, Robert Klopfleisch, Anja Schütz, Hugues Lortat-Jacob, Peter Aichele, Thomas Kammertoens, Thomas Blankenstein
Journal: Nature Immunology (2023)

Abstract Interferon-γ (IFNγ) is an important mediator of cellular immune responses, but high systemic levels of this cytokine are associated with immunopathology. IFNγ binds to its receptor (IFNγR) and to extracellular matrix (ECM) via four positively charged C-terminal amino acids (KRKR), the ECM-binding domain (EBD). Across evolution, IFNγ is not well conserved, but the EBD is highly conserved, suggesting a critical function. Here, we show that IFNγ lacking the EBD (IFNγ ΔKRKR ) does not bind to ECM but still binds to the IFNγR and retains bioactivity. Overexpression of IFNγ ΔKRKR in tumors reduced local ECM binding, increased systemic levels and induced sickness behavior, weight loss and toxicity. To analyze the function of the EBD during infection, we generated IFNγ ΔKRKR mice lacking the EBD by using CRISPR–Cas9. Infection with lymphocytic choriomeningitis virus resulted in higher systemic IFNγ ΔKRKR levels, enhanced sickness behavior, weight loss and fatal toxicity. We conclude that local retention of IFNγ is a pivotal mechanism to protect the organism from systemic toxicity during prolonged immune stimulation.
A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling
Authors: Patricia Altea-Manzano, Ginevra Doglioni, Yawen Liu, Alejandro M. Cuadros, Emma Nolan, Juan Fernández-García, Qi Wu, Mélanie Planque, Kathrin Julia Laue, Florencia Cidre-Aranaz, Xiao-Zheng Liu, Oskar Marin-Bejar, Joke Van Elsen, Ines Vermeire, Dorien Broekaert, Sofie Demeyer, Xander Spotbeen, Jakub Idkowiak, Aurélie Montagne, Margherita Demicco, H. Furkan Alkan, Nick Rabas, Carla Riera-Domingo, François Richard, Tatjana Geukens, Maxim De Schepper, Sophia Leduc, Sigrid Hatse, Yentl Lambrechts, Emily Jane Kay, Sergio Lilla, Alisa Alekseenko, Vincent Geldhof, Bram Boeckx, Celia de la Calle Arregui, Giuseppe Floris, Johannes V. Swinnen, Jean-Christophe Marine, Diether Lambrechts, Vicent Pelechano, Massimiliano Mazzone, Sara Zanivan, Jan Cools, Hans Wildiers, Véronique Baud, Thomas G. P. Grünewald, Uri Ben-David, Christine Desmedt, Ilaria Malanchi, Sarah-Maria Fendt
Journal: Nature Cancer (2023)
Ultrasensitive lateral-flow assays via plasmonically active antibody-conjugated fluorescent nanoparticles
Authors: Rohit Gupta, Prashant Gupta, Sean Wang, Artem Melnykov, Qisheng Jiang, Anushree Seth, Zheyu Wang, Jeremiah J. Morrissey, Ige George, Sumanth Gandra, Pratik Sinha, Gregory A. Storch, Bijal A. Parikh, Guy M. Genin, Srikanth Singamaneni
Journal: Nature Biomedical Engineering (2023)
High- or low-dose preoperative ipilimumab plus nivolumab in stage III urothelial cancer: the phase 1B NABUCCO trial
Authors: Jeroen van Dorp, Christodoulos Pipinikas, Britt B. M. Suelmann, Niven Mehra, Nick van Dijk, Giovanni Marsico, Maurits L. van Montfoort, Sophie Hackinger, Linde M. Braaf, Tauanne Amarante, Charlaine van Steenis, Kirsten McLay, Antonios Daletzakis, Daan van den Broek, Maaike W. van de Kamp, Kees Hendricksen, Jeantine M. de Feijter, Thierry N. Boellaard, Richard P. Meijer, Antoine G. van der Heijden, Nitzan Rosenfeld, Bas W. G. van Rhijn, Greg Jones, Michiel S. van der Heijden
Journal: Nature Medicine (2023)
Landscape of pathogenic mutations in premature ovarian insufficiency
Authors: Hanni Ke, Shuyan Tang, Ting Guo, Dong Hou, Xue Jiao, Shan Li, Wei Luo, Bingying Xu, Shidou Zhao, Guangyu Li, Xiaoxi Zhang, Shuhua Xu, Lingbo Wang, Yanhua Wu, Jiucun Wang, Feng Zhang, Yingying Qin, Li Jin, Zi-Jiang Chen
Journal: Nature Medicine (2023)

Abstract Premature ovarian insufficiency (POI) is a major cause of female infertility due to early loss of ovarian function. POI is a heterogeneous condition, and its molecular etiology is unclear. To identify genetic variants associated with POI, here we performed whole-exome sequencing in a cohort of 1,030 patients with POI. We detected 195 pathogenic/likely pathogenic variants in 59 known POI-causative genes, accounting for 193 (18.7%) cases. Association analyses comparing the POI cohort with a control cohort of 5,000 individuals without POI identified 20 further POI-associated genes with a significantly higher burden of loss-of-function variants. Functional annotations of these novel 20 genes indicated their involvement in ovarian development and function, including gonadogenesis ( LGR4 and PRDM1 ), meiosis ( CPEB1 , KASH5 , MCMDC2 , MEIOSIN , NUP43 , RFWD3 , SHOC1 , SLX4 and STRA8 ) and folliculogenesis and ovulation ( ALOX12 , BMP6 , H1-8 , HMMR , HSD17B1 , MST1R , PPM1B , ZAR1 and ZP3 ). Cumulatively, pathogenic and likely pathogenic variants in known POI-causative and novel POI-associated genes contributed to 242 (23.5%) cases. Further genotype–phenotype correlation analyses indicated that genetic contribution was higher in cases with primary amenorrhea compared to that in cases with secondary amenorrhea. This study expands understanding of the genetic landscape underlying POI and presents insights that have the potential to improve the utility of diagnostic genetic screenings.
Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in a mouse model of Alzheimer’s disease
Authors: Hu Zeng, Jiahao Huang, Haowen Zhou, William J. Meilandt, Borislav Dejanovic, Yiming Zhou, Christopher J. Bohlen, Seung-Hye Lee, Jingyi Ren, Albert Liu, Zefang Tang, Hao Sheng, Jia Liu, Morgan Sheng, Xiao Wang
Journal: Nature Neuroscience (2023)
AMPK-dependent phosphorylation of the GATOR2 component WDR24 suppresses glucose-mediated mTORC1 activation
Authors: Xiaoming Dai, Cong Jiang, Qiwei Jiang, Lan Fang, Haihong Yu, Jinhe Guo, Peiqiang Yan, Fangtao Chi, Tao Zhang, Hiroyuki Inuzuka, John M. Asara, Ping Wang, Jianping Guo, Wenyi Wei
Journal: Nature Metabolism (2023)
Ambient oxygen levels regulate intestinal dysbiosis and GVHD severity after allogeneic stem cell transplantation
Authors: Keisuke Seike, Anders Kiledal, Hideaki Fujiwara, Israel Henig, Marina Burgos da Silva, Marcel R.M. van den Brink, Robert Hein, Matthew Hoostal, Chen Liu, Katherine Oravecz-Wilson, Emma Lauder, Lu Li, Yaping Sun, Thomas M. Schmidt, Yatrik M. Shah, Robert R. Jenq, Gregory Dick, Pavan Reddy
Journal: Immunity (2023)
Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer’s disease-specific cis-regulatory elements
Authors: Ashlyn G. Anderson, Brianne B. Rogers, Jacob M. Loupe, Ivan Rodriguez-Nunez, Sydney C. Roberts, Lauren M. White, J. Nicholas Brazell, William E. Bunney, Blynn G. Bunney, Stanley J. Watson, J. Nicholas Cochran, Richard M. Myers, Lindsay F. Rizzardi
Journal: Cell Genomics (2023)

Cell type-specific transcriptional differences between brain tissues from donors with Alzheimer's disease (AD) and unaffected controls have been well documented, but few studies have rigorously interrogated the regulatory mechanisms responsible for these alterations. We performed single nucleus multiomics (snRNA-seq plus snATAC-seq) on 105,332 nuclei isolated from cortical tissues from 7 AD and 8 unaffected donors to identify candidate
Systematic assessment of prognostic molecular features across cancers
Authors: Balaji Santhanam, Panos Oikonomou, Saeed Tavazoie
Journal: Cell Genomics (2023)

Precision oncology promises accurate prediction of disease trajectories by utilizing molecular features of tumors. We present a systematic analysis of the prognostic potential of diverse molecular features across large cancer cohorts. We find that the mRNA expression of biologically coherent sets of genes (modules) is substantially more predictive of patient survival than single-locus genomic and transcriptomic aberrations. Extending our analysis beyond existing curated gene modules, we find a large novel class of highly prognostic DNA/RNA cis-regulatory modules associated with dynamic gene expression within cancers. Remarkably, in more than 82% of cancers, modules substantially improve survival stratification compared with conventional clinical factors and prominent genomic aberrations. The prognostic potential of cancer modules generalizes to external cohorts better than conventionally used single-gene features. Finally, a machine-learning framework demonstrates the combined predictive power of multiple modules, yielding prognostic models that perform substantially better than existing histopathological and clinical factors in common use.
The <i>Beano</i> , junk food, and public health
Authors: Kamran Abbasi
Journal: BMJ (2023)

The Beano is a success.From its first issue in 1938 to today's multimedia enterprise, the comic has ridden every wave in social norms and publishing strategies.In 2018 it became the world's longest running weekly comic.Today, on beano.com, the comic is only one component of a digital offering that includes over 1000 quizzes, games, jokes, and facts majoring on trends popular among children.
Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer
Authors: Maria Zagorulya, Leon Yim, Duncan M. Morgan, Austin Edwards, Elen Torres-Mejia, Noor Momin, Chloe V. McCreery, Izabella L. Zamora, Brendan L. Horton, James G. Fox, K. Dane Wittrup, J. Christopher Love, Stefani Spranger
Journal: Immunity (2023)
Direct activation of microglia by β-glucosylceramide causes phagocytosis of neurons that exacerbates Gaucher disease
Authors: Takashi Shimizu, Charles R. Schutt, Yoshihiro Izumi, Noriyuki Tomiyasu, Zakaria Omahdi, Kuniyuki Kano, Hyota Takamatsu, Junken Aoki, Takeshi Bamba, Atsushi Kumanogoh, Masaki Takao, Sho Yamasaki
Journal: Immunity (2023)
BRCA1 deficiency in mature CD8<sup>+</sup>T lymphocytes impairs antitumor immunity
Authors: Bogang Wu, Leilei Qi, Huai-Chin Chiang, Haihui Pan, Xiaowen Zhang, Alexandra Greenbaum, Elizabeth Stark, Li-Ju Wang, Yidong Chen, Bassem R. Haddad, Dionyssia Clagett, Claudine Isaacs, Richard Elledge, Anelia Horvath, Yanfen Hu, Rong Li
Journal: Journal for ImmunoTherapy of Cancer (2023)

Women with BRCA1 germline mutations have approximately an 80% lifetime chance of developing breast cancer. While the tumor suppressor function of BRCA1 in breast epithelium has been studied extensively, it is not clear whether BRCA1 deficiency in non-breast somatic cells also contribute to tumorigenesis. Here, we report that mouse Brca1 knockout (KO) in mature T lymphocytes compromises host antitumor immune response to transplanted syngeneic mouse mammary tumors. T cell adoptive transfer further corroborates CD8 + T cell-intrinsic impact of Brca1 KO on antitumor adaptive immunity. T cell-specific Brca1 KO mice exhibit fewer total CD8 + , more exhausted, reduced cytotoxic, and reduced memory tumor-infiltrating T cell populations. Consistent with the preclinical data, cancer-free BRCA1 mutation-carrying women display lower abundance of circulating CD8 + lymphocytes than the age-matched control group. Thus, our findings support the notion that BRCA1 deficiency in adaptive immunity could contribute to BRCA1 -related tumorigenesis. We also suggest that prophylactic boosting of adaptive immunity may reduce cancer incidence among at-risk women.
Ann Robinson’s research reviews—2 February 2023
Authors: Ann Robinson
Journal: BMJ (2023)

Poor scores for risk scoresWe've all got the message by now that there's no point in giving patients their cholesterol result without contextualising it in terms of a risk score.But risk scores are imperfect.This retrospective US study of predictive accuracy found that existing stroke-specific risk prediction models and new machine learning techniques weren't more accurate at predicting new onset strokes than pooled cohort equations.Pooled cohort equations incorporate race and standard cardiovascular risk factors such as sex, age, cholesterol, blood pressure, diabetes, and smoking to give a 10 year risk score, similar to the UK QRisk tool.
Maturational patterns of the infant gut mycobiome are associated with early-life body mass index
Authors: Mackenzie W. Gutierrez, Emily M. Mercer, Shirin Moossavi, Isabelle Laforest-Lapointe, Myrtha E. Reyna, Allan B. Becker, Elinor Simons, Piush J. Mandhane, Stuart E. Turvey, Theo J. Moraes, Malcolm R. Sears, Padmaja Subbarao, Meghan B. Azad, Marie-Claire Arrieta
Journal: Cell Reports Medicine (2023)

Unlike the bacterial microbiome, the role of early-life gut fungi in host metabolism and childhood obesity development remains poorly characterized. To address this, we investigate the relationship between the gut mycobiome of 100 infants from the Canadian Healthy Infant Longitudinal Development (CHILD) Cohort Study and body mass index Z scores (BMIz) in the first 5 years of life. An increase in fungal richness during the first year of life is linked to parental and infant BMI. The relationship between richness pattern and early-life BMIz is modified by maternal BMI, maternal diet, infant antibiotic exposure, and bacterial beta diversity. Further, the abundances of Saccharomyces, Rhodotorula, and Malassezia are differentially associated with early-life BMIz. Using structural equation modeling, we determine that the mycobiome's contribution to BMIz is likely mediated by the bacterial microbiome. This demonstrates that mycobiome maturation and infant growth trajectories are distinctly linked, advocating for inclusion of fungi in larger pediatric microbiome studies.
Small Suspicious Lymph Nodes Detected on Ultrahigh-field Magnetic Resonance Imaging (MRI) in Patients with Prostate Cancer with High Risk of Nodal Metastases: The First In-patient Study on Ultrasmall Superparamagnetic Iron Oxide–enhanced 7T MRI
Authors: Ansje Fortuin, Jack van Asten, Andor Veltien, Bart Philips, Thomas Hambrock, Sören Johst, Stephan Orzada, Boris Hadaschik, Harald Quick, Jelle Barentsz, Marnix Maas, Tom Scheenen
Journal: European Urology (2023)
Improving the study of brain-behavior relationships by revisiting basic assumptions
Authors: Christiana Westlin, Jordan E. Theriault, Yuta Katsumi, Alfonso Nieto-Castanon, Aaron Kucyi, Sebastian F. Ruf, Sarah M. Brown, Misha Pavel, Deniz Erdogmus, Dana H. Brooks, Karen S. Quigley, Susan Whitfield-Gabrieli, Lisa Feldman Barrett
Journal: Trends in Cognitive Sciences (2023)

Neuroimaging research has been at the forefront of concerns regarding the failure of experimental findings to replicate. In the study of brain-behavior relationships, past failures to find replicable and robust effects have been attributed to methodological shortcomings. Methodological rigor is important, but there are other overlooked possibilities: most published studies share three foundational assumptions, often implicitly, that may be faulty. In this paper, we consider the empirical evidence from human brain imaging and the study of non-human animals that calls each foundational assumption into question. We then consider the opportunities for a robust science of brain-behavior relationships that await if scientists ground their research efforts in revised assumptions supported by current empirical evidence.